Células colaboradoras (TH1, TH2, TH17) y reguladoras (Treg,TH3, NKT) en la artritis reumatoide

The immune response foreign antigens require a perfect coordination of cells that participate in its different phases. The objective of the response is the rapid destruction of the microorganisms with a minimum repercussion on self-cells and tissues. The regulation of this process is carried out fundamentally by T lymphocytes. There are two main types of coordinator cells: helper cells, what organize the initial immune response, and regulatory cells, what avoid immune attack against self and once the infection is controlled, disassemble the response. There are three types of helper cells which coordinate answers to intracellular parasites (TH1), helmints (TH2) and extracellular bacteria and fungi (TH17). The hyperfunction of TH17 cells is associated with diseases as reumatoid arthritis, due to the hypersecretion of the proinflammatory citoquine IL17. The condition of helper or regulatory cell is the current object of review. TH1, TH2 and TH17 cells have helper and also regulatory functions.In addition, regulatory T cells play an important role in the coordination of the first moments of the response to viral infection in a direct and indirect way, inducing differentiation of TH17 cells.     

Effect of improved zinc status on T helper cell activation and TH1/TH2 ratio in healthy elderly individuals

Mild zinc deficiency is a common condition in healthy elderly individuals leading to impaired cell-mediated immune response. Here we report the effect of improved zinc status on TH1/TH2 balance and on the activation status of T helper cells in 19 healthy elderly subjects aged 69.8 ± 5.1 years. Our investigations revealed a mild zinc deficiency which was adjusted by oral zinc supplementation for seven weeks. Improved serum zinc levels significantly reduced levels of activated T helper cells whereas changes in TH1/TH2 ratio (determined by CCR4 and CCR5 expression) were not observed. These findings suggest that elderly individuals may benefit from moderate zinc supplementation due to improved immune response leading to reduced incidences of autoimmune diseases and infections.Presented at the Zinc Age Conference, Madrid, Feburary 10–13, 2006.     

CD8+ T cells control the TH phenotype of MBP-reactive CD4+ T cells in EAE mice

Trimolecular interactions between the T cell antigen receptor and MHC/peptide complexes, together with costimulatory molecules and cytokines, control the initial activation of naive T cells and determine whether the helper precursor cell differentiates into either T helper (TH)1 or TH2 effector cells. We now present evidence that regulatory CD8(+) T cells provide another level of control of TH phenotype during further evolution of immune responses. These regulatory CD8(+) T cells are induced by antigen-triggered CD4(+) TH1 cells during T cell vaccination and, in vitro, distinguish mature TH1 from TH2 cells in a T cell antigen receptor Vbeta-specific and Qa-1-restricted manner. In vivo, protection from experimental autoimmune encephalomyelitis (EAE) induced by T cell vaccination depends on CD8(+) T cells, and myelin basic protein-reactive TH1 Vbeta8(+) clones, but not TH2 Vbeta8(+) clones, used as vaccine T cells, protect animals from subsequent induction of EAE. Moreover, in vivo depletion of CD8(+) T cells during the first episode of EAE results in skewing of the TH phenotype toward TH1 upon secondary myelin basic protein stimulation. These data provide evidence that CD8(+) T cells control autoimmune responses, in part, by regulating the TH phenotype of self-reactive CD4(+) T cells.     

TH1 and TH2 cell polarization increases with aging and is modulated by zinc supplementation

Elderly subjects suffer from increased levels of activated T cells and a TH1/TH2 imbalance. Zinc deficiency of the aged is correlated with decreased cell-mediated immune responses. The association of age and zinc adjustment with the amounts of TH1 (CCR5+) and TH2 (CCR4+) cell populations in healthy aged old donors enrolled in the European ZINCAGE project was examined. Old and nonagenarian individuals revealed increased TH1, TH2 cell numbers and a decreased TH2/TH1 ratio in comparison to young individuals. The differences between TH2/TH1 ratios of young and old/nonagenarians arose from young females. Adjusted zinc status led to enhanced TH2 and TH1 amounts in fresh whole blood and thawed cells of aged donors whereas increased HLA-DR+ expression and a generally lower CCR5 expression was observed on thawed PBMC. In conclusion, aging is associated with an increase in T helper cell polarization, and changes in TH2/TH1 subsets are more obvious in women than in men. Advanced healthy aging is accompanied by TH cell polarization, too. Moderate zinc supplementation in vivo alters TH proportions. Longer zinc treatment will give more insight into the beneficial effect of zinc on T helper cell modulation.     

In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations

The morbidity and mortality associated with graft-host-disease (GVHD) is a significant obstacle to the greater use of allogeneic stem cell transplantation. Donor T cells that predominantly differentiate into TH1/Tc1 T cells and generate pro-inflammatory cytokines such as interferon-gamma (IFN-gamma) mediate GVHD. Although numerous studies have described a pathogenic role for IFN-gamma, multiple reports have demonstrated that the lack of IFN-gamma paradoxically exacerbated GVHD lethality. This has led to speculation that another subset of T cells may significantly contribute to GVHD mortality. Several groups have demonstrated a new lineage of CD4+ T helper cell development distinct from TH1 or TH2 differentiation. This lineage is characterized by production of interleukin (IL)-17A, IL-17F, IL-22, and IL-21 and has been termed TH17 cells. Here, we demonstrate that a highly purified population of TH17 cells is capable of inducing lethal GVHD, hallmarked by extensive pathologic cutaneous and pulmonary lesions. Upon transfer, these cells migrate to and expand in GVHD target organs and secondary lymphoid tissues. Finally, we demonstrate differential roles for tumor necrosis factor-alpha (TNF-alpha) and IL-17A in the clinical manifestations of GVHD induced by TH17 cells. Our studies demonstrate that cells other than TH1/Tc1 can mediate acute GVHD.     

Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria

Previous interethnic comparative studies on the susceptibility to malaria performed in West Africa showed that Fulani are more resistant to Plasmodium falciparum malaria than are sympatric ethnic groups. This lower susceptibility is not associated to classic malaria-resistance genes, and the analysis of the immune response to P. falciparum sporozoite and blood stage antigens, as well as non-malaria antigens, revealed higher immune reactivity in Fulani. In the present study we compared the expression profile of a panel of genes involved in immune response in peripheral blood mononuclear cells (PBMC) from Fulani and sympatric Mossi from Burkina Faso. An increased expression of T helper 1 (TH1)-related genes (IL-18, IFNgamma, and TBX21) and TH2-related genes (IL-4 and GATA3) and a reduced expression of genes distinctive of T regulatory activity (CTLA4 and FOXP3) were observed in Fulani. Microarray analysis on RNA from CD4+ CD25+ (T regulatory) cells, performed with a panel of cDNA probes specific for 96 genes involved in immune modulation, indicated obvious differences between the two ethnic groups with 23% of genes, including TGFbeta, TGFbetaRs, CTLA4, and FOXP3, less expressed in Fulani compared with Mossi and European donors not exposed to malaria. As further indications of a low T regulatory cell activity, Fulani showed lower serum levels of TGFbeta and higher concentrations of the proinflammatory chemokines CXCL10 and CCL22 compared with Mossi; moreover, the proliferative response of Fulani to malaria antigens was not affected by the depletion of CD25+ regulatory cells whereas that of Mossi was significantly increased. The results suggest that the higher resistance to malaria of the Fulani could derive from a functional deficit of T regulatory cells.     

Proinflammatory T helper type 17 cells are effective B-cell helpers

T helper type 17 (TH17) cells are highly proinflammatory effector T cells that are characterized by the production of high amounts of IL-17A, IL-17F, IL-21, and IL-22. Furthermore, TH17 cells have been associated with a number of autoimmune diseases. However, it is not clear whether TH17 cells can also serve as effective helper cells. Here we show that TH17 cells can function as B-cell helpers in that they not only induce a strong proliferative response of B cells in vitro but also trigger antibody production with class switch recombination in vivo. Transfer of TH17 cells into WT or T-cell receptor α–deficient mice, which lack endogenous T cells, induces a pronounced antibody response with preferential isotype class switching to IgG1, IgG2a, IgG2b, and IgG3, as well as the formation of germinal centers. Conversely, blockade of IL-17 signaling results in a significant reduction in both number and size of germinal centers. Whereas IL-21 is known to help B cells, IL-17 on its own drives B cells to undergo preferential isotype class switching to IgG2a and IgG3 subtypes. These observations provide insights into the unappreciated role of TH17 cells and their signature cytokines in mediating B-cell differentiation and class switch recombination.     

Plasticity of human Th17 cells and iTregs is orchestrated by different subsets of myeloid cells

CD4+ T helper cell differentiation is essential for mounting robust immune responses without compromising unresponsiveness toward self-tissue. Here, we show that different subsets of myeloid cells isolated from human peripheral blood modulate TGF-β-dependent CD4+ T-cell developmental programs ex vivo. Human CD14+HLA-DR(-/low) myeloid-derived suppressor cells (MDSCs) induce Foxp3+ regulatory T cells, whereas CD14+HLA-DR+ monocytes promote generation of IL-17-secreting RORc+ Th17 cells when cocultured with naive CD4+ T cells. More importantly, not only do these 2 subsets modulate the de novo induction of Tregs and Th17 cells from CD4+ T cells, but MDSCs also catalyze the transdifferentiation of Foxp3+ regulatory T cells from monocyte-induced Th17 cells. The mechanism of such Th17 plasticity is dependent on MDSC-derived TGF-β and retinoic acid. Our results identify a previously unknown feature of the different subsets of CD14+ myeloid cells namely their pivotal role in immune response regulation and plasticity of CD4+ T helper cells. We propose that different subsets of myeloid cells in humans can orchestrate the differentiation of naive CD4+ T cells into effector/regulatory T-cell subsets. The balance between these 2 subsets can impact the outcome of immune reaction from inflammation to tolerance.     

T Helper Cells Profile and CD4+CD25+Foxp3+Regulatory T Cells in Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is considered as the most common cause of female infertility that affects 4-10% of women in the reproductive age. Previous studies have shown the role of a balanced immune response in a successful pregnancy and fertility. Objective: To investigate the T helper cells type 1 (Th1) /Th2/Th17/Treg paradigms in peripheral blood of infertile PCOS compared with normal fertile women. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated at the late follicular phase from 10 PCOS and 10 fertile women. PBMCs were stimulated with PMA and ionomycin in the presence of Berefeldin A as Golgi stop agent to detect intracellular cytokine production (IFN-γ, IL-17, and IL-4) from CD3+CD4+T cells population indicating T helper (Th) cells subsets by flowcytometry. Moreover, regulatory T cells were enumerated using CD25 and Foxp3 markers. Results: In this study, we report that the frequency of Th1 cells was increased compared to Th2 cells in infertile PCOS when considering Th1/Th2 ratio (P=0.05). Analysis of Th17/Th2 ratio showed a significant difference with a bias toward Th17 dominancy in PCOS (P=0.02). The proportion of CD4+CD25+Foxp3+ regulatory T cells was significantly lower in PCOS patients than that of healthy fertile women (P=0.02). Conclusion: In summary, Th1 and Th17 bias and reduction of Treg and Th2 cells as regulators of immune responses might be involved in the pathogenesis of PCOS. These results are suggestive of an altered immune response to inflammatory status in PCOS patients, likely causing some complications such as infertility in these patients.     

Effects of TH1 and TH2 cytokines on CD8+ cell response against human immunodeficiency virus: implications for long-term survival.

CD8+ cells from long-term survivors [LTS; infected with human immunodeficiency virus (HIV) for 10 or more years and having CD4+ cell counts of > or = 500 cells per microliters] have a 3-fold greater ability to suppress HIV replication than do CD8+ cells from patients who have progressed to disease (progressors) during the same time period. A change in the pattern of cytokines produced in the host from those that typically favor cell-mediated immunity (T helper 1, TH1 or type 1) to those that down-regulate it (T helper 2, TH2 or type 2) was investigated as a cause of this reduced CD8+ cell anti-HIV function. Treatment of CD8+ cells from LTS with the TH1 cytokine interleukin (IL)-2 enhanced their anti-HIV activity, whereas exposure of these cells to TH2 cytokines IL-4 or IL-10 reduced their ability to suppress HIV replication and to produce IL-2. IL-2 could prevent and reverse the inhibitory effects of IL-4 and IL-10. Moreover, prolonged exposure of CD8+ cells from some progressors to IL-2 improved the ability of these cells to suppress HIV replication. These observations support previous findings suggesting that strong CD8+ cell responses play an important role in maintaining an asymptomatic state in HIV infection. The data suggest that the loss of CD8+ cell suppression of HIV replication associated with disease progression results from a shift in cytokine production within the infected host from a TH1 to a TH2 pattern. Modulation of these cytokines could provide benefit to HIV-infected individuals by improving their CD8+ cell anti-HIV activity.     

Les lymphocytes TH17 : différenciation, phénotype, fonctions, et implications en pathologie et thérapeutique humaine

Differentiation of naive CD4⁺ T helper (T_H) cells is a major step of the adaptative immune response. When activated by pathogens in a specific cytokine environment, CD4⁺ T cells differentiate into different subsets of T_H cells with specific effector functions. T_H1 lymphocytes orchestrate cellular immune response by producing interferon-γ and stimulating cytotoxic cells whereas T_H2 cells orchestrate humoral immune response by producing interleukin-4 (IL-4), IL-5 and IL-10, leading to immunoglobulin production. Conversely, regulatory T cells (Treg) are capable of inhibiting immune response. Recently discovered, T_H17 cells are characterized by their ability to produce IL-17 and play an important role in anti-infectious and inflammatory immune responses. This review focuses on present knowledge about T_H17 cells: their induction, phenotype, functions, implications in host defense and human disease, and their potential to represent possible therapeutic targets.     

Role and development of TH1/TH2 immune responses in the lungs

The development of T helper 1 (Th1) and Th2 responses is dependent on the cells and early signals of the innate immune system. Following inhalation of pulmonary pathogens, lung antigen-presenting cells (APCs) ingest the microbe, begin to process antigen, and migrate to peripheral lymphoid tissues (i.e., LALNs). It is in the lymph node that the APC-T cell interaction takes place; therefore, the microenvironment of the lymph node significantly influences the developing T cell response (Th1 vs Th2). Several factors can determine the nature of the T cell response, including cytokines, chemokines, microbial virulence factors, and dendritic cell phenotype. A shift in the Th1/Th2 balance in the lungs can result in chronic infection, allergic disease, and immunopathology. This review discusses the mechanisms of developing Th1/Th2 pulmonary responses, the counterregulation of Th1/Th2 immunity, and the consequences of immune deviation in the lungs.     

Th17细胞的生物学特性及其在寄生虫感染中的作用

辅助性T细胞传统上分为Th1型和Th2型.近年研究者发现了一种新的CD4+T细胞亚群,可以产生白细胞介素17(IL-17),被称为Th17细胞.Th17细胞在炎症反应中发挥着重要的调节作用,它的产物IL-17等与原虫、吸虫、绦虫等寄生虫感染有联系.该文就Th17细胞亚群及其产物在寄生虫感染中的作用作一简要综述.     

Human in vitro immune responses to Mycobacterium tuberculosis.

SETTING: T helper cells can be divided into 2 subsets on the basis of their cytokine generation. T helper 1 cells secreting gamma interferon and interleukin 2 appear to be more prominent in patients with limited tuberculous disease. OBJECTIVE: The purpose of this study was to evaluate human T helper cell immune responses to mycobacterial antigens in vitro and correlate these with the clinical features of patients with tuberculous infection or disease. DESIGN: We studied 51 subjects and 11 controls who were grouped according to disease involvement as follows: 1) Mantoux negative, BCG negative, no disease; 2) Mantoux positive, no disease; 3) localized extrapulmonary; 4) healed pulmonary; 5) active pulmonary; and 6) miliary/disseminated. Peripheral blood mononuclear cells were cultured with PHA, PPD or Tetanus Toxoid, proliferation assessed and the supernatant analysed using an ELISA for IFN gamma. ELISA was also used to measure M. tuberculosis specific antibodies in the serum. RESULTS: Mantoux size correlated with PPD proliferation r = 0.5, P = 0.005 and gamma IFN production r = 0.36, P < 0.01. All groups produced abundant gamma IFN although there was a trend toward higher production in groups 3 and 4. M. tuberculosis specific IgA (P = 0.003) and IgG1 (P = 0.002) was higher in groups 5 and 6. Those patients with limited disease (groups 2-4) had significantly lower levels of IgG4 than patients with severe disease (groups 5 & 6) (P < 0.02). CONCLUSION: In conclusion patients with healed or extrapulmonary disease have immune responses in vitro suggestive of a TH1 (cell mediated immune) response, whereas patients with miliary/disseminated disease have antibody production suggestive of a TH2 response, together with high gamma IFN production. Both TH1 and TH2 responses may be necessary for host protection if there is a high bacillary load.     

Dysregulation of mucosal immune response in pathogenesis of inflammatory bowel disease

Inflammatory bowel disease(IBD)includes Crohn’s disease and ulcerative colitis.The exact etiology and pathology of IBD remain unknown.Available evidence suggests that an abnormal immune response against the microorganisms in the intestine is responsible for the disease in genetically susceptible individuals.Dysregulation of immune response in the intestine plays a critical role in the pathogenesis of IBD,involving a wide range of molecules including cytokines.On the other hand,besides T helper(Th)1 and Th2 cell immune responses,other subsets of T cells,namely Th17 and regulatory T cells,are likely associated with disease progression.Studying the interactions between various constituents of the innate and adaptive immune systems will certainly open new horizons of the knowledge about the immunologic mechanisms in IBD.     

Th17/Treg失衡与炎症性肠病的关系

炎症性肠病(inflammatory bowel disease.IBD)的病因和发病机制尚未完全明确,肠道黏膜免疫系统异常反应所导致的炎症过程在发病中起重要作用.辅助性T细胞17(T helper 17 cells,Th17)可介导慢性炎症和自身免疫性疾病的发生,调节性T细胞(regulatory T cell,Treg)有抑制自身免疫的功能,二者存在相互转化的关系.有研究表明Th17/Treg转化平衡是维持肠道免疫稳态的重要因素,这可能是导致人类IBD的原因之一.最近研究表明TGF-β,IL-6和维甲酸(retinoic acid,RA)可能是调控二者平衡关系的重要因素.肠道菌群(intestinal flora)与IBD的发生发展关系密切,益生菌(probiotics)对IBD的治疗作用成为研究的热点.深化对Th17/Treg转化调控关系的研究是当前重要的研究课题.     

Induction of autoimmune thyroiditis by depletion of CD4+CD25+ regulatory T cells in thyroiditis-resistant IL-17, but not interferon-gamma receptor, knockout nonobese diabetic-H2h4 mice

Iodine-induced experimental autoimmune thyroiditis in the nonobese diabetic (NOD)-H2h4 mouse is a prototype of animal models of Hashimoto's thyroiditis in humans. Recent studies have shown the resistance to thyroiditis of NOD-H2h4 mice genetically deficient for either IL-17 or interferon (IFN)-γ, implicating both of T helper type 1 (Th1) and Th17 immune responses in disease pathogenesis. However, we hypothesized that robust induction of a single arm of effector T cells (either Th1 or Th17) might be sufficient for inducing thyroiditis in NOD-H2h4 mice. To address this hypothesis, enhanced immune responses consisting of either Th1 or Th17 were induced by anti-CD25 antibody-mediated depletion of regulatory T cells (Treg) in thyroiditis-resistant IL-17 knockout (KO) or IFN-γ receptor (IFN-γR) KO, respectively, NOD-H2h4 mice. Depletion of Treg in IL-17 KO mice (i.e. Th1 enhancement) elicited antithyroglobulin autoantibodies and thyroiditis. Immunohistochemical analysis of the thyroid glands revealed the similar intrathyroidal lymphocyte infiltration patterns, with CD4+ T and CD19+ B cells being dominant between the wild-type and Treg-depleted IL-17 KO mice. In contrast, Treg-depleted IFN-γR KO mice remained thyroiditis resistant. Intracellular cytokine staining assays showed differentiation of Th1 cells in IL-17 KO mice but not of Th17 cells in IFN-γR KO mice. Our findings demonstrate that a robust Th1 immune response can by itself induce thyroiditis in otherwise thyroiditis-resistant IL-17 KO mice. Thus, unlike Th17 cells in IFN-γR KO mice, Th1 cells enhanced by Treg depletion can be sustained and induce thyroiditis.     

从Th1/Th2、Treg/Th17之间的平衡研究轻、中度慢性乙型肝炎患者CD4~+T淋巴细胞的免疫失衡状态

目的从Th17及其相关细胞因子与Th1、Th2、Treg的相互关系,探讨轻、中度CHB患者CD4~+T淋巴细胞的整体免疫失衡状态。方法选择轻、中度CHB患者,与健康志愿者进行比较,观察其外周血各免疫细胞(Th17、Th1、Th2、Treg、Th1/Th2、Treg/Th17)、相关细胞因子(IL-17、IL-6、TGF-β、IFN-γ、IL-4)、主要效应分子(穿孔素、颗粒酶B)和核转录因子(孤独核受体RORγt、Foxp3等)的变化及其相互关系。结果与健康志愿者相比,CHB患者CD8~+T淋巴细胞比例更高,CD4~+/CD8~+比例显著下降,差异有统计学意义(P0.01);与健康志愿者相比,CHB患者Th1细胞比例更高,Th1/Th2显著升高,差异有统计学意义(P0.01);与健康志愿者相比,CHB患者Th17细胞比例更高,Treg/Th17比例显著下降,差异有统计学意义(P0.01);与健康志愿者相比,CHB患者穿孔素和颗粒酶B的表达更高,差异有统计学意义(P0.01);与健康志愿者相比,CHB患者FOXP3、IL17mRNA和RORγt的表达差异无统计学意义(P0.05);与健康志愿者相比,CHB患者TGF-B1、IL-6、IL-17显著增高,差异有统计学意义(P0.01);IFN-γ和IL-4的表达差异无统计学意义(P0.05)。结论轻、中度CHB患者在免疫细胞及其相关细胞因子、效应分子等各环节,尤其是Treg/Th17比例,均处于严重的免疫失衡状态。